The O’Brien steamed with a convoy for the Western Pacific on 4 February 1942, but she was forced to return when a collision with Case damaged her port side. Following repairs at the Mare Island Navy Yard, the destroyer steamed out again on 20 February, bound for Pearl Harbor. There Commander Destroyer Division 4 shifted his flag to the O’Brien on 5 March 1942.

The O’Brien was retained at Pago Pago for local escort work. On 26 May, she supported the occupation of Wallis Island, previously taken over by the Free French, and then she joined the Procyon on 19 June for the return voyage to Pearl Harbor. Operating out of Pearl Harbor, the ship performed escort duty and acted as patrol and plane guard. She got underway on 17 August with Task Force 17 (TF 17) to reinforce the South Pacific Force, screening the tanker Guadalupe.

Torpedo from I-19 hits O’Brien. USS Wasp can bee seen burning in the background.

At 1452, the O’Brien sighted smoke coming from the USS Wasp. As a member of Hornet's antisubmarine warfare screen, she made an emergency turn to the right. At about 1454, while accelerating and swinging right, her lookouts spotted a torpedo two points forward of the port beam, 1,000 yards (915 meters) away. This torpedo then missed O'Brien close astern, but while her crew's attention was concentrated on it, another torpedo hit her port bow.

This explosion did little obvious damage, but it set up severe structural stresses throughout the framework of the O'Brien. She was able to proceed under her own power, and on 16 September she reached Espiritu Santo, where the sailors of the USS Curtiss made temporary repairs. The USS O’Brien next steamed out on 21 September, bound for Noumea, New Caledonia, for further repairs by the repair ship Argonne. Then, she steamed out on 10 October, bound for San Francisco Bay.

The O'Brien made it to Suva in the New Hebrides on 13 October, and then steamed out once more on 16 October. The rate of leakage of seawater into the O'Brien continued to increase, and on 18 October it was necessary for O’Brien to head for the nearest anchorage. Large amounts of topside weights were jettisoned, and preparations were made for abandoning the ship, but her captain still thought that she could be taken intact to Pago Pago. However, at about 0600 on 19 October, her bottom suddenly split open considerably, and her forward and after hull portions began to work independently. At 0630, all hands except for a small salvage crew abandoned, but half an hour later the O'Brien was abandoned entirely. Just before 0800 she descended beneath the waves, and after steaming nearly 3,000 miles (5,500 km) since she had been torpedoed. All members of her crew were saved.